The present invention relates to a pharmaceutical composition, particularly a tablet composition comprising a high drug load of cinacalcet hydrochloride, having improved bioavailability.

Cinacalcet, having the chemical structure shown above, is a calcimimetic agent, and as such it increases the sensitivity to extracellular calcium of the calcium-sensing receptors of the parathyroid gland, leading to reduced levels of parathyroid hormone, serum calcium, and phosphate. It is indicated for the treatment of secondary hyperparathyroidism in patients with chronic kidney disease on dialysis.
Cinacalcet free base and pharmaceutically acceptable salts thereof are disclosed in European Patent application EP1203761.
A cinacalcet hydrochloride-containing pharmaceutical product is approved in many countries of the world under the brand name Mimpara® (Amgen) in the EU and Sensipar® (Amgen) in the US. Generally, the marketed cinacalcet hydrochloride tablets comprise 30, 60 or 90 mg of cinacalcet hydrochloride.
Cinacalcet hydrochloride is poorly soluble in water and has a pH dependent solubility. At basic pH it is practically insoluble (<0.001 mg/ml). The solubility is about 1.6 mg/ml at a pH range of from about 3-5, however at pH 1 the solubility decreases to approx. 0.1 mg/ml. In the state of the art, various proposals have been made on how to formulate this active pharmaceutical ingredient.
The marketed formulation of cinacalcet hydrochloride is described in WO2005034928. The tablet composition disclosed therein contains cinacalcet hydrochloride with a particle size distribution D50 less than or equal to 50 μm (see paragraph [021]) in an amount of approx. 18% by weight based on the total weight of the tablet composition (see paragraphs [019] and [057]).
The tablet of WO2005034928 contains a high amount (i.e. 70% by weight) of diluent among other pharmaceutical excipients, having a tablet weight of up to 540 mg for the cinacalcet 90 mg tablet strength. The incorporation of a relatively high amount of excipients (e.g., diluents and disintegrants) into the formulation of a solid oral dosage form can improve the dissolution rate of active pharmaceutical ingredients, especially those that are relatively hydrophobic and poorly soluble in water like cinacalcet. Increasing the amount of excipients in the composition, however, entails a number of disadvantages. Notably, tablet size will increase significantly causing patient compliance problems. In addition, content uniformity can be problematic as well as stability problems can occur related to interaction of the active pharmaceutical ingredient with one or more of the excipients.
The objective of the present invention was therefore to overcome the above-mentioned disadvantages.